Glucagon-like peptide-1 (GLP-1) secreted from intestinal L-cells plays a major role in meal termination and glucose-dependent insulin secretion. Several lines of evidence indicate, however, that the acute satiating and incretin effects of GLP-1 are attenuated with high fat diet (HFD) exposure. Here we tested the hypothesis that endogenous GLP-1 differentially affects energy balance and glucose homeostasis dependent on whether rats are fed chow or HFD (60% energy from fat).

We blocked GLP-1 receptor (GLP-1R) signaling by daily intraperitoneal (IP) injection of the GLP-1R antagonist exendin (9–39) (Ex9, 10 μg/kg) or vehicle for 5 weeks in male Sprague-Dawley rats fed either chow or HFD, recorded body weight (BW) and food intake throughout, and assessed energy expenditure (3rd week) and glucose tolerance (4th week).

Five week daily Ex9 injections reduced BW gain in HFD-fed rats, but did not affect BW in chow-fed rats. On the other hand, chronic Ex9 treatment did not affect daily food intake in either chow or HFD-fed rats during the entire study. The reduced BW gain in HFD-fed rats was associated with an increase in energy expenditure. Interestingly, chronic Ex9 treatment induced glucose intolerance in chow-fed rats, but not in HFD-fed rats, suggesting a differential role of GLP-1R signaling in glucose metabolism during chow and HFD feeding.

Our findings reveal a novel role of GLP-1R signaling, modulating energy expenditure rather than eating behavior during HFD feeding. Furthermore, these results suggest a previously unrecognized contribution of GLP-1R signaling to the pathophysiology of obesity.